EP1230901A1 - Mechanical heart valve and production method thereof - Google Patents

Mechanical heart valve and production method thereof Download PDF

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Publication number
EP1230901A1
EP1230901A1 EP00969885A EP00969885A EP1230901A1 EP 1230901 A1 EP1230901 A1 EP 1230901A1 EP 00969885 A EP00969885 A EP 00969885A EP 00969885 A EP00969885 A EP 00969885A EP 1230901 A1 EP1230901 A1 EP 1230901A1
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EP
European Patent Office
Prior art keywords
base body
valve
heart valve
artificial heart
cusp
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Granted
Application number
EP00969885A
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German (de)
French (fr)
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EP1230901B1 (en
EP1230901A4 (en
Inventor
Shinichiro Res. & Dev. Dpt. of Gunze Ltd. MORITA
Saburo Res. & Dev. Dpt. of Gunze Ltd. NAKAMURA
Shigeyuki Res. & Dev. Dpt. of Gunze Ltd. HIRATA
Toshiharu Tokyo Women's Medical Univ. SHIN'OKA
Yasuharu Tokyo Women's Medical University IMAI
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Gunze Ltd
Tokyo Womens Medical University
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Gunze Ltd
Tokyo Womens Medical University
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Publication of EP1230901A4 publication Critical patent/EP1230901A4/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • A61F2/2415—Manufacturing methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • the present invention relates to an artificial heart valve and production method thereof.
  • mitral insufficiency regurgitation
  • aortic stenosis aortic insufficiency
  • tricuspid insufficiency like valvular heart diseases
  • a method for regenerating various kinds of tissues in a living body by employing tissue engineering techniques has recently been developed, wherein cells of autogenous tissue are seeded and cultured on a scaffold made of a bioabsorbable polymer so as to regenerate the autogenous tissues.
  • tissue regeneration method applied to skin regeneration (M. L. Cooper, L. F. Hansbrough, R. L. Spielvogel et al. "In vivo optimization of a living dermal substitute employing cultured human fibroblasts on a biodegradable polyglycolic acid or polyglactin mesh.” Biomaterials 12(1991):243-248) and cartilage regeneration (C.A. Vacanti, R. Langer et al. "Synthetic polymers seeded with chondrocytes provide a template for new cartilage formation.” Plast. Reconstr. Surg. 88(1991):753-759).
  • bioabsorbable substrates which enable the entire heart valve to be made of bioabsorbable material have not yet been developed.
  • An object of the present invention is to provide a practically usable bioabsorbable substrate which enables the entire heart valve to be made of bioabsorbable material.
  • the present invention relates to the artificial heart valves and production methods thereof described below.
  • An artificial heart valve comprising a tubular base body having sinuse(s) of Valsalva and valve cusps provided inside the base body, characterized in that the base body and the valve cusp(s) comprise a bioabsorbable polymer material.
  • Item 2 The artificial heart valve according to item 1, wherein the bioabsorbable polymer material used as a material for the base body and/or the valve cusp(s) contains a reinforcement having a fibrous structure made of a bioabsorbable polymer.
  • Item 3 The artificial heart valve according to item 1, wherein the base body and/or the valve cusp(s) are porous.
  • Item 4 An artificial heart valve formed by seeding living cells into the artificial heart valve according to any one of items 1 to 3.
  • Item 5 A process for producing an artificial heart valve comprising the steps of forming sinuse(s) of Valsalva on a base body and combining valve cusp(s) with the base body.
  • Item 6 The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by adhesion.
  • Item 7 The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by suture.
  • Item 8 The process according to item 7, wherein the suture is conducted using a bioabsorbable suture.
  • Item 9 The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by thermal fusion.
  • Item 10 The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by using a bioabsorbable polymer solution.
  • Item 11 The process according to item 5, wherein the tubular base body having sinuse(s) of Valsalva is formed by molding and one end of a substrate is folded and subjected to heat set so as to form the valve cusp(s).
  • bioabsorbable materials include polyglycolic acid, polylactic acid (D form, L form, DL form), polycaprolactone, glycolic acid-lactic acid (D form, L form, DL form) copolymer, glycolic acid-caprolactone copolymer, lactic acid (D form, L form, DL form)-caprolactone copolymer, poly(p-dioxanone) and like synthetic bioabsorbable polymers, collagen, denatured collagen, gelatin, chitin, chitosan and like natural polymers, etc.
  • the artificial heart valve of the invention comprises a sponge made of bioabsorbable material(s), film, nonwoven fabric and the like.
  • a reinforcement comprising fabric, textile, nonwoven fabric or the like which is also made of a bioabsorbable polymer.
  • the reinforcement and the body of the artificial heart valve may use the same or different bioabsorbable materials.
  • a base body having sinuse(s) of Valsalva can be obtained by pouring a bioabsorbable polymer solution into a mold designed for a base body having a Valsalva sinus structure, freezing and then lyophilizing.
  • the mold can be flat or hollow cylindrical (doughnut-shaped).
  • the obtained sheet-shaped base body can be made tubular by suture, thermal fusion or the like.
  • a base body having a reinforcement can be obtained by following the production steps of setting the fabric, textile, nonwoven fabric or like reinforcement made of a bioabsorbable polymer in the outer mold for the base body having sinuse(s) of Valsalva, pouring a bioabsorbable polymer solution into the cavity, freezing and then lyophilizing.
  • the thus obtained base body is porous.
  • a tubular fabric or textile or a flat fabric or textile is wrapped around a Teflon test tube.
  • the fabric or textile is fused or sutured into a tubular shape.
  • this assembly is set in an outer mold.
  • a bioabsorbable polymer solution forming a substrate is poured into the cavity, frozen and then lyophilized.
  • a porous tubular substrate can be obtained.
  • the tubular substrate is removed from the mold, one of the ends thereof is folded in such a manner that the inner sides thereof attach to each other (in the case of a bicuspid valve, from two directions; and in the case of a tricuspid valve, from three directions), and then the substrate is heat set to obtain valve cusps (Fig. 2).
  • a valve cusp is inserted around the position of the Valsalva sinus in a tubular base body constructed as above. Then, the non-folded end of the valve cusp is sutured to the tubular base body in the vicinity of the Valsalva sinus with a bioabsorbable suture.
  • the thus obtained heart valve substrate is used in the following Examples after being subjected to gas sterilization by ethylene oxide.
  • Living cells endothelial cells, fibroblasts, smooth muscle cells and the like are collected from femoral arteries, grown in mixed-culture and seeded in the artificial heart valve in such a manner that they become endothelial cells.
  • the thus produced heart valve can be implanted in the body of an adult or animal, and is advantageously usable for implantation into an infant or child.
  • the invention provides an artificial heart valve usable in lieu of mechanical, heterograft and homograft heart valves.
  • the artificial heart valve of the invention comprises a bioabsorbable polymer material, it does not remain in vivo as a foreign substance after the tissue has regenerated. When implanted into an infant, it can keep pace with the infant's growth. Furthermore, the porous structure provides excellent adhesiveness for cells.
  • a tubular textile made of polyglycolic acid was set in a mold (20 mm in diameter) designed for a tubular structure having a Valsalva sinus structure 1.
  • the inner mold was put into place from the inside, then a solution of lactic acid-caprolactone copolymer (molar ratio 50 : 50) in dioxane (5 %) was poured into the cavity, frozen at -30 °C and lyophilized at 20 °C for 24 hours.
  • the base body 2 obtained after lyophilization was tubular having a cellular substrate reinforced with a fibrous material in the center (Fig. 7 shows a photograph of a cross-sectional view and Fig. 8 shows a photograph of a plan view).
  • Fig. 1 is an extend elevation showing the tubular structure.
  • a tubular textile made of polyglycolic acid was wrapped around a Teflon test tube having a diameter of 18 mm.
  • This assembly was set in a tubular mold having a diameter of 20 mm, then a solution of lactic acid-caprolactone copolymer (molar ratio 50 : 50) in dioxane (5 %) was poured into the cavity, frozen at -30 °C and lyophilized at 20 °C for 24 hours.
  • the thus obtained valve cusps had a cellular substrate reinforced with a fibrous material in the center (Fig. 9 shows a photograph of a cross-sectional view and Fig. 10 shows a photograph of a plan view).
  • the tricuspid valve 4 as shown in Fig. 2 was obtained by folding the end thereof from three directions, suturing the folded areas together in the center, subjecting them to heat set at 100 °C under vacuum for three hours. After completion of the heat set, the suture was cut.
  • Combination could also be conducted using the sheet-shaped base body 2 shown in Fig. 6, and forming it into tubular form after integrally suturing the Valsalva sinus 1 and the tricuspid valve 4 as described earlier.
  • a valve cusp 4 was set in a tubular structure having a Valsalva sinus structure 1, each apex 5 of the tricuspid valve 4 was integrally sutured with the periphery of Valsalva sinus 1 by polyglycolic acid suture, and then the other end of the tricuspid valve 4 and the base body were integrally sutured in a tubular form, obtaining the artificial heart valve 3 of the invention containing the valve 6.
  • tissue which was isolated in a sterile environment, was immersed in a cell culture medium and washed with phosphate-buffered saline in a clean bench. Then, on a petri dish, the tissue was cut into pieces using a surgical knife according to the simple explant technique. Tissue pieces sized about 1-2 mm 2 were distributed uniformly on the dish and after about 20 minutes, when the tissue pieces intimately adhered to the bottom of the dish, a culture medium was added. This step was carefully conducted so as not to peel off the tissue pieces.
  • DMEM Dulbecco's Modified Eagles Medium
  • antibiotic solution L-glutamine 29.2 mg/ml, penicillin G sodium 1000 U/ml, and streptomycin sulfate 10,000 ⁇ g/ml
  • the lamb vascular wall cells began to migrate from the tissue pieces on the dish after 5-7 days, forming mixed-cell colonies of endothelial cells, fibroblasts, and smooth muscle cells around the explants after one week. After another 2-3 weeks, the mixed-cells became confluent on the dish. Immediately, a passage was made using 0.25 % trypsin and the culture in a 75 cm 2 culture flask was started. When the growth in this flask became confluent, about 2x10 6 cells were generally available. Cell culture was performed in an atmosphere comprising 5 % of CO 2 and 95 % of O 2 and continued until 10x10 6 cells were obtained. When the culture medium was renewed every 4-5 days, the doubling time of cells was about 48 hours.
  • endothelial cells were sorted out from among the mixed-cells using FACS according to the following protocol.
  • Dil-acetylated LDL fluorescent marker; product of Biomedical Technologies
  • Dil-Ac-LDL Dil-Ac-LDL
  • the cells were trypsinized to prepare a mixed-cell suspension and sorting was performed using a cell sorter (FACS machine: product of Bectin Dickenson, Mountainview, California). According to the size and emission of fluorescence, the cells were sorted into Dil-Ac-LDL-positive cells and Dil-Ac-LDL-negative cells.
  • the endothelial cells which are Dil-Ac-LDL-positive cells, represented about 5-8 % of the mixed culture.
  • each type of cells was independently cultured until 2x10 6 endothelial cells were obtained. Incidentally, the counting of the cell population was carried out by the classical exclusion method using Trypan Blue.
  • the heart valve and a valve cusp substrate were seeded with about 2x10 7 Dil-Ac-LDL-negative myofibroblasts.
  • the system was allowed to stand on the culture dish in a clean bench for 30-60 minutes, and thereafter about 50 ml of a culture medium was added.
  • the culture medium was renewed every day as a rule and after 7 days, one day before implantation into an animal body, a further seeding was performed with a suspension of endothelial cells (about 2x10 6 cells), whereby a monolayer of endothelial cells was obtained.
  • a heart valve of a young dog was replaced with the heart valve constructed as above. A good patency was obtained without using an anticoagulant and it was verified that the heart valve of the invention was satisfactorily functioning as a tissue culture heart valve.

Abstract

An artificial heart valve comprising a tubular base body having sinuse(s) of Valsalva and valve cusp(s) provided inside the base body, characterized in that the base body and the valve cusps comprise a bioabsorbable polymer material.

Description

    TECHNICAL FIELD
  • The present invention relates to an artificial heart valve and production method thereof.
    • BACKGROUND ART
  • As observed in mitral stenosis, mitral insufficiency (regurgitation), aortic stenosis, aortic insufficiency, tricuspid insufficiency and like valvular heart diseases, when a heart valve does not properly function and stenosis or regurgitation occurs, the heart valve must be replaced. There are three kinds of heart valves which are currently used in heart transplant operations: (1) mechanical valves, (2) heterograft valves and (3) homograft valves.
  • Mechanical valves have excellent durability; however, they require recipients to take an anticoagulant throughout their lifetime. Heterograft valves, which use valves from animals, do not require recipients to take an anticoagulant throughout their lifetime; however, the valves tend to malfunction after 6 to 10 years. Alternatively, frozen homograft valves harvested from cadavers exhibit more favorable long term results than heterograft valves. Therefore, the frozen homograft valves are widely used in Europe and America where use of cadaver tissue is advanced; however, the drawback of short supply exists.
  • A method for regenerating various kinds of tissues in a living body by employing tissue engineering techniques has recently been developed, wherein cells of autogenous tissue are seeded and cultured on a scaffold made of a bioabsorbable polymer so as to regenerate the autogenous tissues. Quite a few research reports have been published on the tissue regeneration method applied to skin regeneration (M. L. Cooper, L. F. Hansbrough, R. L. Spielvogel et al. "In vivo optimization of a living dermal substitute employing cultured human fibroblasts on a biodegradable polyglycolic acid or polyglactin mesh." Biomaterials 12(1991):243-248) and cartilage regeneration (C.A. Vacanti, R. Langer et al. "Synthetic polymers seeded with chondrocytes provide a template for new cartilage formation." Plast. Reconstr. Surg. 88(1991):753-759).
  • Regeneration of heart valves has also been tested using tissue engineering techniques and a study regarding regeneration of heart valve leaflets has reported good results (T. Shin'oka et. al. "Tissue-engineered heart valve leaflets. Autologous valve leaflet replacement study in a lamb model." Circulation 94 (suppl. II) (1996):II-164-II-168. T. Shin'oka et al. "Tissue-engineered heart valve leaflets. Does cell origin affect outcome?" Circulation 96 (suppl. II) (1996): II-102-II-107).
  • However, practically usable bioabsorbable substrates which enable the entire heart valve to be made of bioabsorbable material have not yet been developed.
  • An object of the present invention is to provide a practically usable bioabsorbable substrate which enables the entire heart valve to be made of bioabsorbable material.
    • BRIEF DESCRIPTION OF DRAWINGS
  • Fig. 1 is an extend elevation showing a tubular structure having sinuses of Valsalva.
  • Fig. 2 shows a tricuspid valve.
  • Fig. 3 is a cross-sectional view of an artificial heart valve of the invention.
  • Fig. 4 is a plan view of an artificial heart valve of the invention.
  • Fig. 5 is a perspective view of an artificial heart valve of the invention.
  • Fig. 6 shows a tricuspid valve 4 integrally sutured with sinuses of Valsalva 1 on a sheet-shaped base body 2.
  • Fig. 7 is a photograph showing a cross-sectional view of the tubular structure.
  • Fig. 8 is a photograph showing a plan view of the tubular structure.
  • Fig. 9 is a photograph showing a cross-sectional view of a tubular used for forming a valve cusp.
  • Fig. 10 is a photograph showing a plan view of tubular substrate used for forming a valve cusp.
    • DISCLOSURE OF INVENTION
  • The present invention relates to the artificial heart valves and production methods thereof described below.
  • Item 1. An artificial heart valve comprising a tubular base body having sinuse(s) of Valsalva and valve cusps provided inside the base body, characterized in that the base body and the valve cusp(s) comprise a bioabsorbable polymer material.
  • Item 2. The artificial heart valve according to item 1, wherein the bioabsorbable polymer material used as a material for the base body and/or the valve cusp(s) contains a reinforcement having a fibrous structure made of a bioabsorbable polymer.
  • Item 3. The artificial heart valve according to item 1, wherein the base body and/or the valve cusp(s) are porous.
  • Item 4. An artificial heart valve formed by seeding living cells into the artificial heart valve according to any one of items 1 to 3.
  • Item 5. A process for producing an artificial heart valve comprising the steps of forming sinuse(s) of Valsalva on a base body and combining valve cusp(s) with the base body.
  • Item 6. The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by adhesion.
  • Item 7. The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by suture.
  • Item 8. The process according to item 7, wherein the suture is conducted using a bioabsorbable suture.
  • Item 9. The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by thermal fusion.
  • Item 10. The process according to item 5, wherein the combining of the valve cusp(s) with the base body is conducted by using a bioabsorbable polymer solution.
  • Item 11. The process according to item 5, wherein the tubular base body having sinuse(s) of Valsalva is formed by molding and one end of a substrate is folded and subjected to heat set so as to form the valve cusp(s).
  • Examples of bioabsorbable materials include polyglycolic acid, polylactic acid (D form, L form, DL form), polycaprolactone, glycolic acid-lactic acid (D form, L form, DL form) copolymer, glycolic acid-caprolactone copolymer, lactic acid (D form, L form, DL form)-caprolactone copolymer, poly(p-dioxanone) and like synthetic bioabsorbable polymers, collagen, denatured collagen, gelatin, chitin, chitosan and like natural polymers, etc.
  • The artificial heart valve of the invention comprises a sponge made of bioabsorbable material(s), film, nonwoven fabric and the like. When the artificial heart valve of the invention must have a certain level of strength, it can be reinforced by a reinforcement comprising fabric, textile, nonwoven fabric or the like which is also made of a bioabsorbable polymer.
  • The reinforcement and the body of the artificial heart valve may use the same or different bioabsorbable materials.
  • For preparation of the heart valve, the following alternative processes, among others, are available.
    • (1) Production of Valsalva sinus
  • A base body having sinuse(s) of Valsalva can be obtained by pouring a bioabsorbable polymer solution into a mold designed for a base body having a Valsalva sinus structure, freezing and then lyophilizing. The mold can be flat or hollow cylindrical (doughnut-shaped). When the mold for the base body is flat, the obtained sheet-shaped base body can be made tubular by suture, thermal fusion or the like.
  • A base body having a reinforcement can be obtained by following the production steps of setting the fabric, textile, nonwoven fabric or like reinforcement made of a bioabsorbable polymer in the outer mold for the base body having sinuse(s) of Valsalva, pouring a bioabsorbable polymer solution into the cavity, freezing and then lyophilizing. The thus obtained base body is porous.
    • (2) Production of valve cusps (inner valve)
  • A tubular fabric or textile or a flat fabric or textile is wrapped around a Teflon test tube. The fabric or textile is fused or sutured into a tubular shape. Then, this assembly is set in an outer mold. Thereafter, a bioabsorbable polymer solution forming a substrate is poured into the cavity, frozen and then lyophilized. Thus, a porous tubular substrate can be obtained. The tubular substrate is removed from the mold, one of the ends thereof is folded in such a manner that the inner sides thereof attach to each other (in the case of a bicuspid valve, from two directions; and in the case of a tricuspid valve, from three directions), and then the substrate is heat set to obtain valve cusps (Fig. 2).
    • (3) Combination
  • A valve cusp is inserted around the position of the Valsalva sinus in a tubular base body constructed as above. Then, the non-folded end of the valve cusp is sutured to the tubular base body in the vicinity of the Valsalva sinus with a bioabsorbable suture. The thus obtained heart valve substrate is used in the following Examples after being subjected to gas sterilization by ethylene oxide.
    • (4) Culture and seeding of cells
  • Living cells (endothelial cells, fibroblasts, smooth muscle cells and the like) are collected from femoral arteries, grown in mixed-culture and seeded in the artificial heart valve in such a manner that they become endothelial cells.
    • (5) Implantation
  • The thus produced heart valve can be implanted in the body of an adult or animal, and is advantageously usable for implantation into an infant or child.
  • The invention provides an artificial heart valve usable in lieu of mechanical, heterograft and homograft heart valves.
  • Because the artificial heart valve of the invention comprises a bioabsorbable polymer material, it does not remain in vivo as a foreign substance after the tissue has regenerated. When implanted into an infant, it can keep pace with the infant's growth. Furthermore, the porous structure provides excellent adhesiveness for cells.
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • The following example is further illustrative of the present invention.
    • Example 1 (1) Production of tubular structure
  • A tubular textile made of polyglycolic acid was set in a mold (20 mm in diameter) designed for a tubular structure having a Valsalva sinus structure 1. The inner mold was put into place from the inside, then a solution of lactic acid-caprolactone copolymer (molar ratio 50 : 50) in dioxane (5 %) was poured into the cavity, frozen at -30 °C and lyophilized at 20 °C for 24 hours. The base body 2 obtained after lyophilization was tubular having a cellular substrate reinforced with a fibrous material in the center (Fig. 7 shows a photograph of a cross-sectional view and Fig. 8 shows a photograph of a plan view). Fig. 1 is an extend elevation showing the tubular structure.
    • (2) Production of valve cusps
  • A tubular textile made of polyglycolic acid was wrapped around a Teflon test tube having a diameter of 18 mm. This assembly was set in a tubular mold having a diameter of 20 mm, then a solution of lactic acid-caprolactone copolymer (molar ratio 50 : 50) in dioxane (5 %) was poured into the cavity, frozen at -30 °C and lyophilized at 20 °C for 24 hours. The thus obtained valve cusps had a cellular substrate reinforced with a fibrous material in the center (Fig. 9 shows a photograph of a cross-sectional view and Fig. 10 shows a photograph of a plan view). The tricuspid valve 4 as shown in Fig. 2 was obtained by folding the end thereof from three directions, suturing the folded areas together in the center, subjecting them to heat set at 100 °C under vacuum for three hours. After completion of the heat set, the suture was cut.
  • Combination could also be conducted using the sheet-shaped base body 2 shown in Fig. 6, and forming it into tubular form after integrally suturing the Valsalva sinus 1 and the tricuspid valve 4 as described earlier.
    • (3) Combination
  • A valve cusp 4 was set in a tubular structure having a Valsalva sinus structure 1, each apex 5 of the tricuspid valve 4 was integrally sutured with the periphery of Valsalva sinus 1 by polyglycolic acid suture, and then the other end of the tricuspid valve 4 and the base body were integrally sutured in a tubular form, obtaining the artificial heart valve 3 of the invention containing the valve 6.
    • (4) Cell culture A. Cell isolation, culture, and propagation
  • About 2 cm of femoral artery was collected from a 20-day-old Dover lamb under general anesthesia while preserving the deep femoral artery intact. The tissue, which was isolated in a sterile environment, was immersed in a cell culture medium and washed with phosphate-buffered saline in a clean bench. Then, on a petri dish, the tissue was cut into pieces using a surgical knife according to the simple explant technique. Tissue pieces sized about 1-2 mm2 were distributed uniformly on the dish and after about 20 minutes, when the tissue pieces intimately adhered to the bottom of the dish, a culture medium was added. This step was carefully conducted so as not to peel off the tissue pieces.
  • As the culture medium, Dulbecco's Modified Eagles Medium (DMEM) supplemented with 10 % fetal bovine serum and 1 % antibiotic solution (L-glutamine 29.2 mg/ml, penicillin G sodium 1000 U/ml, and streptomycin sulfate 10,000 µg/ml) was used.
  • The lamb vascular wall cells (mixed-cells) began to migrate from the tissue pieces on the dish after 5-7 days, forming mixed-cell colonies of endothelial cells, fibroblasts, and smooth muscle cells around the explants after one week. After another 2-3 weeks, the mixed-cells became confluent on the dish. Immediately, a passage was made using 0.25 % trypsin and the culture in a 75 cm2 culture flask was started. When the growth in this flask became confluent, about 2x106 cells were generally available. Cell culture was performed in an atmosphere comprising 5 % of CO2 and 95 % of O2 and continued until 10x106 cells were obtained. When the culture medium was renewed every 4-5 days, the doubling time of cells was about 48 hours.
    • B. Cell sorting and endothelial cell purification
  • At the stage when the mixed-cells became confluent and a reasonable number of cells was obtained, endothelial cells were sorted out from among the mixed-cells using FACS according to the following protocol. Dil-acetylated LDL (fluorescent marker; product of Biomedical Technologies) (briefly, Dil-Ac-LDL) was added to the mixed-cell culture at a concentration of 1 µg/ml, followed by 24-hour incubation. This marker was taken up intracellularly through a scavenger pathway specific to endothelial cells and macrophages. After 24 hours, the cells were trypsinized to prepare a mixed-cell suspension and sorting was performed using a cell sorter (FACS machine: product of Bectin Dickenson, Mountainview, California). According to the size and emission of fluorescence, the cells were sorted into Dil-Ac-LDL-positive cells and Dil-Ac-LDL-negative cells. The endothelial cells, which are Dil-Ac-LDL-positive cells, represented about 5-8 % of the mixed culture. After sorting, each type of cells was independently cultured until 2x106 endothelial cells were obtained. Incidentally, the counting of the cell population was carried out by the classical exclusion method using Trypan Blue.
    • C. Structure of leaflets
  • The heart valve and a valve cusp substrate were seeded with about 2x107 Dil-Ac-LDL-negative myofibroblasts. Immediately following the seeding of a concentrated cell suspension on the matrix, the system was allowed to stand on the culture dish in a clean bench for 30-60 minutes, and thereafter about 50 ml of a culture medium was added. The culture medium was renewed every day as a rule and after 7 days, one day before implantation into an animal body, a further seeding was performed with a suspension of endothelial cells (about 2x106 cells), whereby a monolayer of endothelial cells was obtained.
    • D. Animal experiment
  • A heart valve of a young dog was replaced with the heart valve constructed as above. A good patency was obtained without using an anticoagulant and it was verified that the heart valve of the invention was satisfactorily functioning as a tissue culture heart valve.

Claims (11)

  1. An artificial heart valve comprising a tubular base body having sinuse(s) of Valsalva and valve cusp(s) provided inside the base body, characterized in that the base body and the valve cusp(s) comprise a bioabsorbable polymer material.
  2. The artificial heart valve according to claim 1, wherein the bioabsorbable polymer material used as a material for the base body and/or the valve cusp(s) contains a reinforcement having a fibrous structure made of a bioabsorbable polymer.
  3. The artificial heart valve according to claim 1, wherein the base body and/or the valve cusp(s) are porous.
  4. An artificial heart valve formed by seeding living cells into the artificial heart valve according to any one of claims 1 to 3.
  5. A process for producing an artificial heart valve comprising the steps of forming sinuse(s) of Valsalva on a base body and combining valve cusp(s) with the base body.
  6. The process according to claim 5, wherein the combining of the valve cusp(s) with the base body is conducted by adhesion.
  7. The process according to claim 5, wherein the combining of the valve cusp(s) with the base body is conducted by suture.
  8. The process according to claim 7, wherein the suture is conducted using a bioabsorbable suture.
  9. The process according to claim 5, wherein the combining of the valve cusp(s) with the base body is conducted by thermal fusion.
  10. The process according to claim 5, wherein the combining of the valve cusp(s) with the base body is conducted by using a bioabsorbable polymer solution.
  11. The process according to claim 5, wherein the tubular base body having sinuse(s) of Valsalva is formed by molding and one end of a substrate is folded and subjected to heat set so as to form the valve cusp(s).
EP00969885A 1999-10-22 2000-10-19 Mechanical heart valve and production method thereof Expired - Lifetime EP1230901B1 (en)

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JP30163299A JP2001120582A (en) 1999-10-22 1999-10-22 Artificial cardiac valve and method of manufacturing the same
JP30163299 1999-10-22
PCT/JP2000/007265 WO2001030274A1 (en) 1999-10-22 2000-10-19 Mechanical heart valve and production method thereof

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WO2006031436A1 (en) * 2004-09-10 2006-03-23 Cook Incorporated Prosthetic valve with pores
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DE60022075T2 (en) 2006-06-29
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EP1230901B1 (en) 2005-08-17
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DE60022075D1 (en) 2005-09-22
US6875230B1 (en) 2005-04-05

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